4-aryl-piperidine-ketones and a process of preparing them



" Patented July 1,1941

UNlTED STATE s PATENT OFFICE d-ARYL-PIPERIDINE-KETONES AND A PROCESS OFPREPARING THEM om Eisleb, lioiheim in rammed-many, as-

signor to New York, N. 1.,

Winthrop Chemical Company, Inc

a corporation of N w York No Drawing. Application April 6, 1940, SerialNo.

' 328,373. In Germany March 30, 1939 Claims.

The present invention relates to 4-aryl-piperidine-ketones and to aprocess or preparing them. U. 8. Patent No. 2,167,351 relates amongothers to t-aryl-piperidine-i-carboxylic acid nitriles the generalformula wherein Ar stands for aryl and R for a monovalent hydrocarbonradical I have found that these nitriles may be transformed in anexcellent yield into 4-aryl-piperidyl- 4-ketones by reacting them withmagnesium organic compounds and decomposing the intermediate productsthus obtained with dilute acids. The reaction takes place according tothe following scheme:

In the store-given scheme Ar stands for an aryl radical, particularlyfor a phenyl radicaL-R stands for a hydrocarbon radical, particularlyior an having 1 to 6 carbon atoms and Big stands for halogen.

As starting material there may be used for instance the1-methyl-4-phenyl-piperidine-4-carboxylic acid nitrile and; thel-benzyl-i-phenylpiperidine-4-carboxylic acid-nitrile.

The new compounds have the property not hitherto noticed in basicallysubstituted ketones of being highly antispasmodic and acting as goodanodyne remedies; they are, thei efore, valuable remedies possessing atthe same time a low toxicity.

The following examples serve to illustrate the invention, but they arenot intended to limit it thereto, the parts being by weight: I

1. 1-methyl-4-phenyl piperidyl-4-methyl-ket0n A solution ofmethyl-magnesium iodide prepared irom 71 parts of methyl iodide and 12parts of 'magnesium turnings in 200 parts oi ether is added to asolution of 80 parts of lsmethyl-4-phenyl-piperidine-4-carboxylic acidnitrile in 200 parts of toluene. The heat produced is not essential;when self-heating no longer occurs the mixture is heated on thewater-bath at the descending condenser; the ether distils and thetoluene solution is kept for 3 hours at the temperature of thewater-bath. The decomposition occurs by pouring thesolution on ice andstirring it with dilute hydrochloric acid of which such a v quantity hasto be applied that an acid reaction to Congo paper is maintained duringthe operation. A crystalline magma ofl-methyl-a-phenylpiperidyl-4-methylketone-hydroiodide is obtained whichis sparingly soluble in cold water, filtered with suction, washed withether and recrystallized from hot water. The yield amounts to 83' partsof colorless crystals melting at 219 C. to 222 C;

Thebase separated from the hot aqueous solution of the salt withpotassium carbonate boils, after having been taken up in ether and driedover potassium carbonate, at 143 C. under a pressure of 3.5 mm. 0ncooling it solidifies; its solidification point is at 54 C. The base israther readily soluble in water.

2. 1-methyl-4- nen -meriduz-4ethyl-Jeanne A solution of ethyl-magnesiumbromide prepared irom '55 parts of ethyl bromide and 12 parts ofmagnesium in 200parts of ether is added to a solution 0!, parts ofl-meth'yl-s-phenylpiperidine-4-carboxylic acid nitrile in 200 parts oftoluene. The mixture is further treated as described in Example 1.During the decomposition with ice and hydrochloric acid no saltseparates in the present case. The base is therefore precipitated in theform of an oil by supersaturating the solution which is just acid toCongo paper with ammonia; it is then taken up in ether, dried overpotassium carbonate and distilled. Boiling-point at 145 C. under apressure oi 3 mm. The yield amounts to 76 parts. The base is a colorlessoil. The hydrochloride is a colorless crystalline powder melting at C.;

it readily dissolves in water. The crime-base slight selfheating occurs.

again and melts.

at 135 C. The oxime hydrochloride constitutes colorless crystals meltingat 227 C. to 228 C.

3. 1-methyl-4-phenyl-piperidyl 4-phenyl- Icetone A solution ofphenyl-magnesium bromide prepared from -78 parts of bromobenzene and 12'grams of magnesium in 200 parts of ether is added to 60 parts of1-methyl-4-pheny1-piperidine-4-carboxylic acid nitrile; only a very Anoil precipitates which on boiling the mixture in a reflux condenser soonsolidifies and forms a crystalline. mass. After having boiled theproduct for 3 hours it is decomposed with ice and hydrochloric acid. The

' salt solution acid to Congo paper which has been separated from theether solution is precipitated with ammonia in excess. The base is takenup in ether, dried over potassium carbonate and dis tilled. Itsboilingpoint is at 199 C. under a pressure of 4 mm. The base is a veryviscous, very ieebly yellowish oil and 'is readily soluble in petroleumether and methyl alcohol. n addition of water it first precipitates frommethyl alcohol in the form of an oil, but it soon solidifies as thehydrate. Its melting point is at 79 C';-80 C. On drying under reducedpressure over sulfuric acid the hydrate gives off its water Thehydrochloride is a color, less crystalline powder melting at 243 C. to244 C. while assuming a dark coloration; it readily dissolves in water.

4. -1-methyl-4-phenul-piperidyl-4-benzylketone A solution of benzylmagnesium chloride prepared from 64 parts of benzyl chloride and 12 6.1-cyclohezyl-4-phenyl-p'iperidyl-4- ethyl-ketone If in theprecedingExample 5the '83 parts of l-benzyl-4-phenyl-piperidine 4carboxylic acid nitrile are replaced by 84 parts ofl-cyclohexyl-4-phenyl-piperidine-4-carboxylic acid ni-.

:trile and the process is otherwise carried through in the same manneras in Example 5, the 1 cyclohexyl-4-phenyl-piperidyl-4-ethylketonehydrochloride is obtained. The salt may be recrystallized from Water; itforms colorless crystals melting at 245 C. to 246 C. The yield amountsto 85 parts. The free base melts at 80 C.

In ananalogous manner-there may be obtained from 1-methyl-4-phenyl-plperidine-4- carboxylic acid nitrile by the action ofpropylmagnesium-bromide the 1-methyl-4-phenyl-piperidyl-4-propyl-ketone,base, colorless oil, boiling at 159 C.-165 C. under a pressure of 5 mm.;

hydrochloride, colorless crystalline powder melt- 4 ing at115 C. to 1170., phosphate, colorless crystalline powder melting at 152 C. to 157 0.;

from isopropyl-magnesium-bromide the 1-methyl-4-phenyl-piperidyl-4-isopropyl-ketone, colorless oil boiling at 167C. to 168 C. under a. pressure of 7 mm.; phosphate, colorlesscrystalline powdermel-ting at 199 C. to 202 C.; fromallylmagnesium-bromide the l-methyl 4 phenylpiperidine-4-allyl-ketone,boiling at 166 C. to 170 C. under a pressure of 3 mm.;-hydrochloride,colorless crystals melting at 193 C. to 196 C.

' from isobutyl-magnesium-chloride the l-methyl parts 01! magnesium in200 parts of ether is i added to 80 parts ofv1-methyl-4-phenyl-piperidine-4-carboxylic acid nitrile which has beendissolved in 200 'parts of toluene. After the mixture has been boiledfor 10 minutes in a reflux condenser the ether is distilled on the waterbath a and the solution of toluene is kept for 3 hours at thetemperature of the water bath. The solution is then decomposed bypouring it on ice and adding hydrochloric acid until the reaction isconstantly acid to Congo paper. A thick crystalline precipitate isproduced consisting of the hydrochloride of ketone which after havingbeen stirred for some time is fllteredwith suction, while cold, washedwith ether and ice-cold water. After drying the product at 140 C. the

- yield amounts to 114 parts. The melting point is at l88fjC.'-190 C.The hydrochloride is hardly soluble in cold water but readily solubleinhot water, rather readily soluble in methyl alcohol and ethyl alcohol.The base precipitated from the aqueous solution of the salt with ammoniarapidly solidifies; itmelts at 53 C. to 55 C. 5.1-'benzyl-4-phenyl-piperidzll-4-ethyl- A solution ofethyl-magnesium-bromide preto a solution of 83 parts of1-benzyl-4-pheriylpiperidine-4-carboxylic acid nitrile in partsoftoluene. The ether is then distilled on the wa-.

. cyclohexyl-k'etone, viscous oil boiling at 192 C. to

200 C. under a pressure of 5 mm. hydrochloride,

4-phenyl-piperidyl-4-isobutyl-ketone, oil boilingat C. to C. under apressure of 5 mm.; phosphate, colorless crystalline powder melting at166 C. to 167 C.; from hexyl-magnesiumbromide the1-methyl-4-phenyl-piperidy1- 4 n-hexyl-ketone, oil boiling at 183 C. to186C.

,- under a pressure of 4 mm.; phosphate crystallizes from water ascolorless crystals containing crystal water; fromcyclohexyl-magnesiumbromide the 1-methyl-4-phenyl-piperidyl-4- colorlesscrystalline powder, decomposition point above 204 C.; from4-methoxyphenyl-magnesium-bromidethe I-methyl-bphenyl-piperidyl- 4-(4,methoxy-phenyl)-ketone, boiling over at about 215 C. under apressureof 2 mm. as an oil whichon cooling solidifies in a glossy form;

hydrochloride, colorless crystalline powder melting at 237 C. to 238 C.;frombeta-phenylethyl-magnesium-chlorlde the1-methyl-4-phenyl-piperidyl-4-beta-phenyl ethyl-ketone hydrochloridecrystallizes from water so as to contain crystal water. Melting point 75C. to 78 C.

. pared from 12 parts of-magnesium and 55 parts v of ethyl bromide in300 parts of ether is added I claim: 7 1 1. The process which comprisesreacting a compound of the'following formula v .u- /CNY HaC OH:

wherein'Ar-stands for aryl" and R stands for a hydrocarbon radical witha magnesium-organic compound and treating the intermediate product Ithus obtained with a dilute acid.

2. The process which comprises reacting a compound of the followingformula 3. The process which comprises reacting a compound of thefollowing formula with a compound of the general formula: R-MgHJgwherein R stands for a hydrocarbon radical and Big stands for halogenand treating the intermediate product thus obtained with a dilute acid.v

4. The process which comprises reacting a compound of thefollowingformula can CN with a compound of the general formula R-Mg-Hlg wherein Rstands for an alkyl radical of 1 to fi'carbon atoms and Hlg stands forhalogen and treating the intermediate product thus obtained with adilute acid;

5. The products of the following formula -Ar CO.R

c 'HIO C E! El H I wherein Ar stands for aryl and R stands for ahydrocarbon radical.

6. The products of the following Cull; CO.R

formula wherein R stands for a hydrocarbon radical. "I. The products ofthe following formula 0.1:. con I JIHs wherein It stands for an alkylradical of 1 to 6 carbon atoms.

8. 1-methy1-4-phenyl piperidyl 4- methylketone;

9. 1-methyl-4-phenyl-piperidyi 4 ethyl kc,-

tone.

10. 1 methyl-4-phenyl piperidyl 4 phenylketone.

O'I'I'O EISLEB.

